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WO1996015127A1 - Composes de pyridazinoquinoleine - Google Patents

Composes de pyridazinoquinoleine Download PDF

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Publication number
WO1996015127A1
WO1996015127A1 PCT/GB1995/002613 GB9502613W WO9615127A1 WO 1996015127 A1 WO1996015127 A1 WO 1996015127A1 GB 9502613 W GB9502613 W GB 9502613W WO 9615127 A1 WO9615127 A1 WO 9615127A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
hydroxy
chloro
quinoline
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1995/002613
Other languages
English (en)
Inventor
Thomas Michael Bare
Marc Jerome Chapdelaine
Timothy Wayne Davenport
James Roy Empfield
Laura Enid Garcia-Davenport
Paul Francis Jackson
Jeffrey Alan Mckinney
Charles David Mclaren
Richard Bruce Sparks
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Syngenta Ltd
Original Assignee
Zeneca Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to NZ294918A priority Critical patent/NZ294918A/xx
Priority to DE69526106T priority patent/DE69526106T2/de
Priority to MX9703139A priority patent/MX9703139A/es
Priority to EP95936046A priority patent/EP0790996B1/fr
Priority to AT95936046T priority patent/ATE215085T1/de
Priority to AU38132/95A priority patent/AU705938B2/en
Application filed by Zeneca Ltd filed Critical Zeneca Ltd
Priority to JP8515817A priority patent/JPH10508617A/ja
Publication of WO1996015127A1 publication Critical patent/WO1996015127A1/fr
Priority to FI971971A priority patent/FI971971A7/fi
Priority to NO972153A priority patent/NO308899B1/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis

Definitions

  • This invention relates to pyridazineone compounds useful in the treatment of neurological disorders generally in mammals such as man. More specifically, the compounds are useful in the treatment of strokes and/or other neurodegenerative disorders such as hypoglycemia, cerebral palsy, transient cerebral ischemic attack, perinatal asphyxia, epilepsy, psychosis, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease,
  • Olivo-pontocerebellar atrophy viral-induced neurodegeneration such as in acquired immunodeficiency syndrome and its associated dementia, anoxia such as from drowning, spinal cord and brain trauma, and chronic pain, for the prevention of drug and alcohol withdrawal symptoms, and for the inhibition of tolerance and dependence to opiate analgesics.
  • the invention particularly relates to novel pyridazineone compounds useful in reducing neurological degeneration such as can be induced by a stroke and the associated functional impairment which can result.
  • Treatment using a compound of the invention can be remedial or therapeutic as by administering a compound following an ischemic event to mitigate the effects of that event. Treatment can also be prophylactic or prospective by administering a compound in anticipation that an ischemic event may occur, for example in a patient who is prone to stroke.
  • ischemic events can trigger a dramatic increase in extracellular concentrations of the excitatory amino acids glutamate and aspartate which can, in turn, cause prolonged neuronal excitation leading to a massive influx of calcium from extracellular to intracellular sites in brain neural cells.
  • a calcium overload can thereby be created which leads to a cascade of events leading to cell catabolism and eventually resulting in cell death.
  • the N-methyl-D-aspartate (NMDA) receptor complex is believed to play a significant role in the cascade of events leading to cell necrosis following an ischemic event.
  • the compounds provided by this invention may be useful in a variety of neurodegenerative disorders because they function as excitatory amino acid antagonists.
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five-or six-membered ring selected from phenyl, pyridyl, furyl, pyrrolyl or thienyl either unsubstituted or multi-substituted at a ring carbon atom with R 4 wherein R 4 is independently selected from the group consisting of halo, (1-4C)alkyl, NO 2 , CN, (C1-3)perfluoroalkyl, OH,
  • R 1 is selected from H, or -(CH 2 ) n L wherein L is M or W;
  • M is phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from-O-(1-4C)alkyl, -O-(2-4C)alkenyl, -O-(2-4C)alkynyl, -O(C0-C6alkyl)phenyl, -OH, -halo, -NO 2 , -CN, -CF 3 , -(1-4C)alkylCF 3 , -NH(CO)R', -(1-4C)alkyl, -NR'R", -CO 2 R', -CONR'R", -SO m R', -SO 2 NR'R", (C1-C6)alkyloxy (C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryl
  • W is selected from OH, OR', OCOR', S(O) m R', S(O) m NR'R", halo,CF 3 NR'R" with the proviso that NR'R" is not equal to NH 2 ; or W is
  • n for groups other than W, is chosen from 0-6; 2
  • R is selected from H or -(CH 2 ) n L wherein L is M or W and
  • M is: phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2 or 3 groups chosen from -O-(1-4C)alkyl, -OH, -halo, -NO 2 , -CN, -CF 3 , -NH(CO)R', -(1-4C)alkyl, -NR'R", -CO 2 R', -CONR'R", -SO m R', -SO 2 NR'R", (C1-C6)alkyloxy (C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy-,
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2,or 3
  • W is selected from OH, OR', OCOR', S(O) m R', halo, S(O) m NR'R",NR'R" with the proviso that NR'R" is not equal to NH 2 ; or W is COR', NR'COR", OCONR', NR'CO 2 R", (C3-6)cycloalkyl, NRCONR'R", CO 2 R', or CONRR' with the proviso that n is greater than zero and; n; for groups other than W, is chosen from 0-6;
  • R is selected from H, (1-6C)alkyl or (1-6C)alkylaryl wherein aryl may be substituted with a substituent or substituents selected from halogen, C1-6alkyl or other typical aromatic substituents;
  • R is selected from -(CO)R 6 wherein R 6 is selected from (1) hydrogen, (2) (1-12C)alkyl which may contain a double or triple bond, and which may bear a group selected from (a) CN, OR e , and CO 2 R e , wherein R e is selected from hydrogen, (1-4C)alkyl, and phenyl and phenyl (1-4C)alkyl the phenyl rings of which can be substituted with from 0-3
  • each R f is independently selected (1) from R h , COR h , and COOR h when the said group is NR f 2 and (2) from the values of R h when the said group is CONR f 2 , wherein R h can have any of the values stated above for R e , or wherein, for either of the said groups, the two R f values, together with the nitrogen to which they are attached, form a saturated 4- to 7-membered ring, (3) NR g 2 wherein each R g can independently have any of the values stated above for R e , or wherein the two R g groups together with the nitrogen to which are are attached form a saturated 4- to 7-membered ring, (4) pyridyl, pyridyl (1-12C)alkyl, (5) phenyl, and phenyl (1-4C)alkyl
  • R is selected from H or (1-4C)alkyl
  • R' and R" are independently selected from H, (1-4C)alkyl wherein alkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); (3-6C)cycloalkyl,
  • the present invention also relates to a compound of formula B (formula set out herein) or pharmaceutically acceptable salts thereof: wherein:
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, -furyl, pyrrolyl or thienyl either unsubstituted or multi-substituted at a ring carbon atom with R 4 wherein R 4 is independently selected from the group consisting of halo, (1-4C)alkyl, NO 2 , CN, (C1-3)perfluoroalkyl, OH,
  • R 1 is selected from H or -(CH 2 ) n L wherein L is M or W;
  • M is phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from
  • heterocycle wherein heterocycle is selected from a five- and/or six-and/or seven-membered heterocyclic ring containing 1,2, or 3
  • W is selected from OH, OR', OCOR', S(O) m R', S(O) m NR'R", halo,CF 3 NR'R" with the proviso that NR'R" is not equal to NH 2 ; or W is COR',
  • NR'COR OCONR', NR'CO 2 R", (C3-6)cycloalkyl, NRCONR'R", CO 2 R', or CONRR' with the proviso that n is greater than zero and;
  • n for groups other than W, is chosen from 0-6;
  • R 3 is selected from H or -C(O)R 6 wherein R 6 is selected from
  • (1-12C) alkyl which may contain a double or triple bond
  • R is selected from H or (1-4C) alkyl
  • R' and R" are independently selected from H, (1-4C) alkyl wherein alkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); (3-6C)cycloalkyl,
  • the present invention further relates to a compound of formula B and pharmaceutically acceptable salts thereof wherein:
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted at one or more ring carbon atoms with R 4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO 2 , CN,
  • R 1 is -(CH 2 ) n L wherein
  • L is chosen from:
  • oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(1-4C)alkyl,
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2, or 3
  • heteroatoms chosen from O, N, or S wherein the N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heterocycle may be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with 0 to form a carbonyl group or sulfonyl group (S(O) m ); wherein the heterocyclic groups may be selected from, for example, 2-pyrolidinone, piperazine, oxazolidone,
  • orthobenzoicsulfimide either unsubstituted or mono, bi or
  • heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group
  • substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to -(CH 2 ) n via a carbon atom or a heteroatom on the heteroaryl group; n is 0-3; R, R 3 , R 6 , R', R" and m are as previously defined.
  • the present invention further relates to a compound of formula B and pharmaceutically acceptable salts thereof wherein: Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted at one or more ring carbon atoms with R 4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO 2 , CN,
  • R 1 is -(CH 2 ) n L wherein
  • L is chosen from: phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from
  • oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner
  • aryloxy (1-4C)alkyloxy(1-4C) alkyl aryloxy (1-4C)alkyloxy(1-4C) alkyl
  • heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substituents include typical aromatic
  • the invention relates to a compound of formula B or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted at one or more ring carbon atoms with R 4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO 2 , CN,
  • R 1 is -(CH 2 ) n L wherein
  • L is chosen from:
  • NR'COR OCONR', NR'CO 2 R", NRCONR'R", CO 2 R', or CONRR'; phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from -O-(1-4C)alkyl, -O-(2-4C)alkenyl, -O-(2-4C)alkynyl,
  • oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(1-4C)alkyl,
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2, or 3
  • heterocycle may be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with 0 to form a carbonyl group or sulfonyl group (S(O) m ); wherein the heterocyclic groups may be selected from, for example, 2-pyrolidinone, piperazine, oxazolidone,
  • orthobenzoicsulfiraide either unsubstituted or mono, bi or
  • heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substituents include typical aromatic
  • substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to "(CH 2 ) via a carbon atom or a heteroatom on the heteroaryl group; n is 1; R, R 3 , R 6 , R', R" and m are as previously defined.
  • the invention also relates to a compound of formula B or
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted at one or more ring carbon atoms with R 4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO 2 , CN,
  • R 1 is "(CH 2 ) n L wherein
  • L is chosen from:
  • NR'COR OCONR', NR'CO 2 R", NRCONR'R", CO 2 R', or CONRR'; phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from
  • oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(1-4C)alkyl,
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2,or 3
  • heteroatoms chosen from O, N, or S wherein the N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heterocycle may be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with 0 to form a carbonyl group or sulfonyl group (S(O) m ); wherein the heterocyclic groups may be selected from, for example, 2-pyrolidinone, piperazine, oxazolidone,
  • orthobenzoicsulfimide either unsubstituted or mono, bi or
  • heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group
  • substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to -(CH 2 ) n via a carbon atom or a heteroatom on the heteroaryl group; n is 2; R, R 3 , R 6 , R', R" and m are as previously defined.
  • the invention further relates to a compound of formula B or
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted at one or more ring carbon atoms with R 4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C) alkyl, NO 2 , CN,
  • R 1 is -(CH 2 ) n L wherein
  • L is chosen from:
  • NR'COR OCONR', NR'CO 2 R", NRCONR'R", CO 2 R', or CONRR'; phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from
  • oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(1-4C)alkyl,
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2, or 3
  • heteroatoms chosen from O, N, or S wherein the N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heterocycle may be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with 0 to form a carbonyl group or sulfonyl group (S(O) m ); wherein the heterocyclic groups may be selected from, for example, 2-pyrolidinone, piperazine, oxazolidone,
  • orthobenzoicsulfimide either unsubstituted or mono, bi or
  • alkyl or aromatic substituents including -halo, -C1-C6alkyl, -OH, C1-C6alkoxy,- phenyl, OCF 3 , CF 3 , NO 2 , CN, NH 2 , SO m R',
  • heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substituents include typical aromatic
  • substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to -(CH 2 ) n via a carbon atom or a heteroatom on the heteroaryl group; n is 3; R, R 3 , R 6 , R', R" and m are as previously defined.
  • the invention also relates to a compound of formula B or
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted at one or more ring carbon atoms with R 4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO 2 , CN,
  • R 1 is -(CH 2 ) n L wherein
  • L is chosen from:
  • oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner
  • aryloxy (1-4C)alkyloxy (1-4C)alkyl 1-4C
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2, or 3
  • heteroatoms chosen from O, N, or S wherein the N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heterocycle may be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with 0 to form a carbonyl group or sulfonyl group (S(O) m ); wherein the heterocyclic groups may be selected from, for example, 2-pyrolidinone, piperazine, oxazolidone,
  • orthobenzoicsulfimide either unsubstituted or mono, bi or
  • heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, iraidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroary
  • the present invention also relates to a compound of formula T' wherein A, R 4 , R 1 and R 3 are as defined for those variables in formulae A or B and pharmaceutical compositions and methods of use thereof as recited for compositions and compounds of formula A.
  • the present invention further relates to a compound of formula U wherein A, R 4 , R 1 and R 3 are as defined for those variables in formula A or B and further wherein R' or R" are selected independently from H or
  • the present invention also relates to pharmaceutical compositions of formula U and methods of use as recited herein for compounds or compositions of formulae A or B.
  • the present invention also relates to an intermediate compound of formula D or D 1
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted at one or more ring carbon atoms with R 4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO 2 , CN,
  • X is halogen; and n is 1-4; R 3 , R, R', R" and m are as previously defined.
  • the present invention may also relate to intermediate compounds of formula E or F wherein F is defined as E except R 1 is bonded to N instead of M,
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted at one or more ring carbon atoms with R 4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO 2 , CN,
  • M for compound E and n equal to 0, is chosen from phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from -O-(1-4C)alkyl, -O-(2-4C)alkenyl,
  • heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substituents include typical aromatic
  • R 1 is selected from H or -(CH 2 ) n L wherein L is M or W; M is phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from
  • oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner
  • aryloxy (1-4C)alkyloxy(1-4C) alkyl aryloxy (1-4C)alkyloxy(1-4C) alkyl
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2, or 3
  • W is selected from OH, OR', OCOR', S(O) m R', S(O) m NR'R", halo, NR'R", COR', NR'COR", OCONR', NR'CO 2 R", (C3-6)cycloalkyl, NRCONR'R", CO 2 R', or CONRR' and; n is chosen from 1-4;
  • R is selected from H or (1-4C)alkyl or Bz;
  • R' and R" are independently selected from H, (1-4C)alkyl wherein alkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); (3-6C)cycloalkyl,
  • the present invention may also relate to a compound of formula G or H wherein:
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, furyl, pyrrolyl or thienyl either unsubstituted or multi-substituted at a ring carbon atom with R 4 wherein R 4 is independently selected from the group consisting of halo, (1-4C)alkyl, NO 2 , CN, (C1-3)perfluoroalkyl, OH,
  • R 1 is selected from H or -(CH 2 ) n L wherein L is M or W;
  • M is phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from
  • oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(1-4C)alkyl,
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2, or 3
  • W is selected from OH, OR', OCOR', S(O) m R', S(O) m NR'R", halo, NR'R" with the proviso that NR'R" is not equal to NH 2 ; or W is COR',
  • NR'COR OCONR', NR'CO 2 R", (C3-6)cycloalkyl, NRCONR'R", CO 2 R', or CONRR' with the proviso that n is greater than zero and; n, for groups other than W, is chosen from 0-4;
  • R is selected from H or (1-4C)alkyl
  • R' and R when on the group R1, are independently selected from H, (1-4C)alkyl wherein alkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); (3-6C)cycloalkyl, Phenyl (0-4C)alkyl-, heterocycle (0-4C)alkyl- or heteroaryl (0-4C)alkyl- wherein phenyl or heterocycle or heteroaryl is as defined above and any of the above is optionally substituted at one or more carbon atoms with halo, H, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, NO 2 , CN, CF 3 , OH, O-(1-4C)alkyl, NR'R" S(O) m R' or SO 2 NR'R" wherein NR'R" may optionally form an N-alkyl(C1-3)oxyalkyl(C2-3) ring with N; or, when directly attached to the amide nitrogen on formula G,
  • the invention further relates to compounds of the formula A or A 1 :
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, furyl, pyrrolyl or thienyl either unsubstituted or substituted at a ring carbon atom with
  • R 4 wherein R 4 is independently selected from the group consisting of halo, (1-4C)alkyl, NO 2 , CN, (C1-3)perfluoroalkyl, OH, OCF 3 ,
  • R is selected from H, (1-6C)alkyl, or -(CH 2 ) n L wherein L is M or W; M is phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen independently from
  • oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(1-4C)alkyl,
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-merabered heterocyclic ring containing 1,2, or 3
  • W is selected from OH, OR', OCOR', S(O) m R', S(O) m NR'R", halo, CF 3 ,
  • NR'R with the proviso that NR'R" is not equal to NH 2 ; or W is COR', NR'COR", OCONR', NR'CO 2 R", (C3-6)cycloalkyl, NRCONR'R", CO 2 R', or CONRR' with the proviso that n is greater than zero and; n, for groups other than W, is chosen from 0-6;
  • R 2 is selected from H or -(CH 2 ) n L wherein L is M or W and
  • M is: phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2 or 3 groups independently chosen from
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2,or 3
  • W is selected from OH, OR', OCOR', S(O) m R', halo, S(O) m NR'R",NR'R" with the proviso that NR'R" is not equal to NH 2 ; or, W is COR',
  • NR'COR OCONR', NR'CO 2 R", (C3-6)cycloalkyl, NRCONR'R", CO 2 R', or CONRR' with the proviso that n is greater than zero and; n, for groups other than W, is chosen from 0-6;
  • R 5 is selected from H, (1-6C)alkyl or (1-6C)alkylaryl wherein aryl may be substituted with a substituent or substituents selected
  • R 3 is selected from H or -(CO)R 6 wherein R 6 is selected from (1) hydrogen, (2) (1-12C)alkyl which may contain a double or triple bond, and which may bear a group selected from (a) CN, OR e , and CO 2 R e , wherein R e is selected from hydrogen, (1-4C)alkyl, and phenyl and phenyl (1-4C)alkyl the phenyl rings of which can be substituted with from 0-3 substituents selected from halo, amino, hydroxy, cyano, nitro, (1-4C)alkyl, and (1-4C)alkoxy; (b) NR f 2 , and CONR f 2 wherein each R f is independently selected (1) from R h , COR h , and COOR h when the said group is NR f 2 and (2) from the values of R h when the said group is CONR f 2 , wherein R h can have any of the values stated above for R e , or
  • each R g can independently have any of the values stated above for R e , or wherein the two R g groups together with the nitrogen to which are are attached form a saturated
  • R is selected from H or (1-4C)alkyl
  • R' and R" are independently selected from H, (1-4C)alkyl (wherein alkyl includes alkenyl(C2-C4) and alkynyl(C2-C4)); (3-6C)cycloalkyl, Phenyl (0-4C)alkyl-, heterocycle (0-4C)alkyl- or heteroaryl (0-4C)alkyl- wherein phenyl or heterocycle or heteroaryl is as defined above and any of the above is optionally substituted at .one or more carbon atoms with halo, H, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, NO 2 , CN, CF 3 , OH, O-(1-4C)alkyl, NR'R", S(O) m R' or SO 2 NR'R" wherein NR'R" may optionally form an N-alkyl(C1-3)oxyalkyl(C2-3) ring with N; and m is chosen from 0-2
  • Ring A is chosen from phenyl, or pyridyl either unsubstituted or substituted at a ring carbon atom with R 4 wherein R 4 is independently selected from the group consisting of halo, (1-4C))alkyl, NO 2 , CN,
  • R is selected from H, (1-6C)alkyl or -(CH 2 ) n L wherein L is M or W;
  • M is phenyl which is either unsubstituted of substituted with 1, 2, 3 or 4 groups chosen independently from -O-(1-4C)alkyl,
  • M is heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species (a) chosen from pyridyl, thienyl, or furanyl, or (b) those groups containing two heteroatoms selected from N, O, or S which are chosen from pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, pyridazine, pyrimidine or pyrazine, wherein the substituted aromatic substituents are selected from hydroxy, alkoxy, halo or cyano and wherein the heteroaryl group is attached to -(CH 2 ) via a carbon atom; W is selected from OH, OR', S(O) m R', (S(O) m NR'R", halo, CF 3 or NR'R"; n is chosen from 0-6;
  • R 3 is selected from H, or -(CO) R 6 wherein R 6 is selected from (1)
  • (1-12C)alkyl which may bear a group selected from CN, OR e , and CO 2 R e , wherein R e is selected from hydrogen, (1-4C)alkyl, and phenyl; and (2) phenyl and phenyl (1-4C)alkyl;
  • R' and R" are independently selected from H, (1-4C)alkyl, and phenyl (0-4C)alkyl- wherein phenyl is optionally substituted at one or more carbon atoms with halo, (1-4C)alkyl, NO 2 , CN, CF 3 , OH, or
  • n is chosen from 0-2.
  • Preferred compounds of the formula B above are those wherein:
  • Ring A is phenyl either unsubstituted or substituted at a ring carbon atom with R 4 wherein R 4 is independently selected from the group consisting of halo, (1-4C)alkyl and O(1-4C)alkyl;
  • R 1 is selected from H, (1-6C)alkyl, or -(CH 2 ) n L wherein L is M or W;
  • M is phenyl which is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen independently from -O-(1-4C)alkyl, -O(C 0 -C 6 alkyl)phenyl, -OH, -halo, -CN, -CF 3 or -(1-4C)alkyl; or
  • M is heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species chosen from pyridyl, thienyl or furanyl, wherein the substituted aromatic substituents are selected from hydroxy, or alkoxy;
  • W is selected from OH, OR', S(O) m R', or NR'R"; n is chosen from 0-6;
  • R 3 is selected from H, or -(CO)R 6 wherein R 6 is selected from (1) (1-4C)alkyl which may bear a group selected from CO 2 R e wherein R e is (1-4C)alkyl and (2) phenyl;
  • R' and R" are independently selected from H, (1-4C)alkyl and
  • R 3 and m are as defined directly above;
  • Ring A is phenyl either unsubstituted or substituted at one to two ring carbon atoms with R 4 wherein R 4 is halo;
  • R 1 is selected from H, (1-6C)alkyl, or -(CH 2 ) n L wherein L is M or W;
  • M is phenyl which is either unsubstituted or substituted with 1 or 2 groups chosen independently from -O(1-4C)alkyl, -O(C 0 -C 6 alkyl)phenyl, -OH, -halo, -CN, -CF 3 , or -(1-4C)alkyl; or
  • M is heteroaryl wherein heteroaryl is pyridyl or pyridyl substituted by one alkoxy group;
  • W is selected from OH, S(O) m R', or NR'R"; n is 0-2; and
  • R' and R" are independently selected from H, (1-4C)alkyl, and phenyl (0-4C)alkyl- wherein phenyl is optionally substituted at one carbon atom with 0-(1-4C)alkyl.
  • W; n and m are as defined directly above;
  • Ring A is phenyl substituted at one to two ring carbon atoms with R 4 wherein R 4 is chloro;
  • R 1 is selected from H, butyl, 1-methylbutyl, hexyl, or (CH 2 ) n L wherein
  • L is M or W
  • M is phenyl which is either unsubstituted or substituted with 1 or 2 groups chosen independently from methoxy, phenoxy, -OH, fluoro, bromo, chloro, -CN, -CF 3 , or methyl; or
  • M is heteroaryl wherein heteroaryl is pyridyl substituted by one methoxy group
  • R 3 is selected from H, or -(CO) R 6 wherein R 6 is selected from methyl, ethyl, methoxycarbonylethyl, and phenyl;
  • R' and R" are independently selected from H, methyl, ethyl and phenyl substituted at one carbon atom with methoxy.
  • Preferred species of the formula B above are those which are described hereinafter on pages 58-59.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula A and a pharmaceutically acceptable excipient or diluent.
  • It further relates to a pharmaceutical composition comprising a compound of formula B and a pharmaceutically acceptable excipient or diluent and to a pharmaceutical composition comprising a compound according to formula A', B', C or C and a pharmaceutically acceptable excipient or diluent.
  • the invention further relates to a method for the treatment of neurological disorders comprising administering to a mammal in need of such treatment an effective amount of a compound of the formula A, A' or B.
  • the invention further relates to the use of a compound of the formula A, A' or B for the preparation of a medicament for the treatment of neurological disorders.
  • the present invention also relates to a method of treating or preventing ischemic damage in a patient in need of such treatment comprising administering a pharmaceutically effective amount of a compound of formula B to said patient.
  • the invention further relates to a method of treating or preventing neurological damage associated with excitatory amino acids in a patient in need of such treatment comprising administering a
  • the invention also relates to a method of treating stroke or epileptic convulsions or diseases or disorders associated with excessive calcium influx in the brain caused by excitatory amino acids comprising administering to a patient in need of treatment thereof a
  • the invention further relates to a process for producing a compound of formula B or B', comprising: treating any of the compounds produced in steps (a)-(i) with a reducing agent under suitable conditions to form a compound of formula B and further treating a compound of formula B with a reducing agent under the appropriate conditions to form a compound of formula B' or treating a compound produced in steps (a)-(i) with a reducing agent under the appropriate conditions to form a compound of formula B' wherein steps (a)-(i) comprise:
  • the invention further relates to a process for producing a compound of formula B according to certain steps recited above as shown in the examples wherein the compounds are selected from:
  • the invention also relates to the use of a compound of formula B or B' in medicine and to diseases or disorders associated with excitatory amino acids.
  • the invention also relates to the use of a compound of formula B or B for the treatment of stroke or epileptic convulsions or disorders or conditions associated with excessive influx of. calcium ions in the brain.
  • the present invention also relates to compounds which are useful as key intermediates in the production of glycine receptor antagonists as defined above wherein W is equal to halo species such as Cl, Br, F or I wherein n is greater than zero.
  • W is equal to halo species such as Cl, Br, F or I wherein n is greater than zero.
  • compounds obtained through a novel process for the production of pyridazinoquinolines as herein defined with R 1 selected from aryl or heteroaryl as defined above are key intermediates in the production of said compounds.
  • These key intermediates are 3-carboalkoxy quinoline 2-carboxylic acid N-2-aryl (or heteroaryl) hydrazides which are used to produce the above aryl or heteroaryl species wherein aryl and heteroaryl are as defined above.
  • 3-carboxylic acid quinoline 2-pyrrolidineamide intermediates which are utilized to react with BOC-protected aryl, heteroaryl or substituted alkyl hydrazines to form after coupling with dicyclohexyldiimide or diisopropyldiimide, in a polar solvent such as THF, methanol, diethylether, dioxane, CH 2 Cl 2 , CH 3 CN or DMF and an acid (e.g.
  • the pyrrolidine may be substituted with an
  • thieno[2',3':5,6]pyrido[2,3-d]pyridazine-5,8,9(4H,6H,7H)-trione and (2) thieno[3',2':5,6]pyrido[2,3-d]pyrid-azine-4,5,8(6H,7H,9H)-trione are known, for example from J. Heterocyclic Chem., 28, 205, (1991).
  • pyridazinedione compounds are known from, for example, Beilstein's Handbuch der Organischen Chemie; Godard et. al., Bull. Soc. Chim. Fr., 1588, (1972); and Reid et. al., Chem. Ber., 85, 204, (1952).
  • the compounds of the present invention relate to novel 2- or 3-substituted pyridazinediones or tautomers thereof as shown above in formula A or A'.
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted at one or more ring carbon atoms with R 4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO 2 , CN, (C1-3)perfluoroalkyl, OH, OCF 3 , (2-4C)alkenyl, (2-4C)alkynyl,
  • R 1 is -(CH 2 ) n L wherein
  • L is chosen from:
  • NR'COR OCONR', NR'CO 2 R", NRCONR'R”, CO 2 R', or CONRR' with the proviso that n is greater than zero;
  • aryl or benz derivatives thereof either unsubstituted or mono, bi or tri-substituted with aromatic substituents including -halo,
  • heteroaryl or N(C1-C4alkyl) 2 ; heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2,or 3
  • heteroatoms chosen from O, N, or S wherein the N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heterocycle may be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with 0 to form a carbonyl group or sulfonyl group (S(O) m ); wherein the heterocyclic groups may be selected from, for example, 2-pyrolidinone, piperazine, oxazolidone,
  • heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group
  • substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to -(CH 2 ) n via a carbon atom or a heteroatom on the heteroaryl group;
  • R 3 is H; and n is 0-3; and pharmaceutically acceptable salts thereof.
  • the present invention also relates to pharmaceutical compositions of a compound of formula B as defined above and a pharmaceutically acceptable excipient.
  • the present invention relates to important intermediates which are useful in the synthesis of a compound of formula B wherein L in the above formula is chosen from halo (Br, Cl, F or I) and n is greater than zero. This intermediate is useful in the production of certain glycine receptor antagonists of formula B.
  • a compound of formula C In the case of a compound of formula C,
  • Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or multi-substituted at a ring carbon atom with R4 wherein R 4 is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO 2 , CN,
  • R 2 is - (CH 2 ) n L wherein
  • L is chosen from:
  • heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2, or 3
  • substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to -(CH 2 ) n via a carbon atom on the heteroaryl group;
  • R 3 is H; n is 0-3; and pharmaceutically acceptable salts thereof.
  • the present invention also relates to pharmaceutical compositions of a compound of formula C as defined above and a pharmaceutically acceptable excipient.
  • the present invention relates to important intermediates which are useful in the synthesis of a compound of formula C wherein L in the above formula is chosen from halo (Br, Cl, F or I). This intermediate is useful in the production of certain glycine receptor antagonists of formula C.
  • Ring A is chosen from phenyl or substituted phenyl wherein the phenyl ring is mono, di or tri-substituted with halo, nitro or simple
  • C1-C4alkyl including methyl, ethyl or propyl
  • R 1 in the case of formula B, is chosen from -(CH 2 ) n L wherein
  • L is chosen from:
  • NR'COR OCONR', NR'CO 2 R", NRCONR'R”, CO 2 R', or CONRR' with the proviso that n is greater than zero;
  • aryl or benz derivatives thereof either unsubstituted or mono, bi or tri-substituted with aromatic substituents including -halo,
  • CF 3 OCF 3 , NO 2 , CN, NH 2 , -C(O)NR'R", heteroaryl, SO m R', NH(C1-4alkyl), or N(C1-C4alkyl) 2 ;
  • succinimide ; oxazolidone; piperazine or substituted versions thereof wherein the substients are selected from (C1-4alkyl), phenyl including substituted phenyl wherein the phenyl substituents are typical aromatic substituents, 2-pyrolidinone and substituted versions thereof
  • C4-6alkyl 2,4-thiazolidinedione, 2,4-imidazolidinedione or substituted versions thereof (e.g. alkyl, dialkyl, phenyl,
  • benz or heteroaryl benz derivatives thereof selected from phthalimido, orthobenzoicsulfimide, isatoic anhydride or 3,4
  • R 3 is H; n is 0-3; and pharmaceutically acceptable salts including the choline salts thereof.
  • R 2 in the case of formula C with ring A as defined above, is chosen from -(CH 2 ) n L wherein
  • L is chosen from:
  • n is equal to 0 and L is chosen from 4-S(O) m R' Phenyl wherein m is 0-2, 2-methylphenyl, 2-methyl,4-chlorophenyl,
  • the present invention relates to compounds of formula B or pharmaceutically acceptable salts thereof wherein
  • Ring A is chosen from an ortho fused phenyl, 7-chlorophenyl, 7, 9-dichlorophenyl, 7-chloro-9-methylphenyl, 7-methyl, 9-chlorophenyl, 7, 9-dimethylphenyl, 7-chloro-8-nitrophenyl,
  • R 1 is selected from -(CH 2 ) n L wherein
  • L is selected from: -OH, -O(C1-C4alkyl), -O(C1-C4alkyl)aryl,
  • substituted phenyl wherein the phenyl substituents are typical aromatic substituents; 2,5-oxazolidinedione and substituted versions thereof selected from C1-C6alkyl, phenyl or substituted
  • phenyl,C3-C6spiralalkyl pyrrolidone and substituted versions thereof selected from C1-C6alkyl, hydroxy, phenyl; 2,4-imidazolidinedione or substituted versions thereof selected from C1-C6alkyl, phenyl or substituted phenyl; 2,4-thiazolidinedione or substituted versions thereof selected from C1-C6alkyl or phenyl; or benz or heteroaryl benz heterocyclic derivatives selected from -1-phthalimide,
  • orthobenzoicsulfimide isatoic anhyrdride or 3,4-dicarboximide
  • heteroaryl selected from thiophene, imidazole, triazole, tetrazole furan or pyridine; R is H and n is 0-2.
  • n is equal to zero, R 3 is H and L is selected from: phenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-methylphenyl, 4-isopropylphenyl, napthyl, 4-flourophenyl, 4-bromophenyl, 2-methoxyphenyl,
  • 2,4-dichlorophenyl 4-nitrophenyl,2,5-dimethoxyphenyl,2,5-dimethylphenyl, 4-oxybenzylphenyl, 2,5-dihydroxyphenyl, 4-vinylphenyl, 2,5-diflourophenyl, 2-methyl-4-flourophenyl, 3, 5-dimethoxyphenyl, 4-carboxyphenyl, 4-formamidophenyl, 4-(N,N-diethylformamido)phenyl, 4-cyanophenyl, or 4-tetrazolephenyl.
  • the present invention also relates to compounds of formula.
  • n is equal to 1
  • R is H and L is selected from any of the members identified above for n equal to zero and, more particularly to groups selected from 1-flourophenyl, 4-cyanophenyl, 4-triflouromethylphenyl,
  • n is equal to three and L is selected from any group designated for n equal to zero or one, but more particularly to a group selected from phenyl or a phenyl substituted with a typical aromatic substituent.
  • the substituted alkyl (C1-6)aryls disclosed herein which are particularly useful are those containing phenyl substituents which increase lipophilicity to enhance red nucleus activity.
  • the flourinated, alkylflourinated, alkyl (C1-4) or mono-halogenated benzyl compounds have enhanced activity.
  • the (C1-C6) alkyl groups substituted with a terminal CF, group are particularly useful because of their unexpected solubility properties and are also useful because of their lipophilicity.
  • the pyridyl rings attached via a carbon atom on the pyridyl ring to the (CH 2 )n group of a compound of formula B have glycine receptor antagonist activity.
  • the present invention also preferrably relates to a compound of formula B wherein n is equal to two, R 3 is H and a heterocyclic moiety as described herein is bonded to the N-2-ethyl carbon and is selected from 1-phthalimido, 4-phenylpiperazine,succinimide,3,
  • orthobenzoicsulfimide sacharine
  • 4-cyclochexylspira1,2,5-oxazolidinedione isatoic anhydride,benzole] [1,3]oxazine-2,4-dione
  • heterocycle include groups selected from tetrahydrofuran, piperidine,
  • the present invention also preferrably relates to compounds of formula B wherein R 1 is equal to (CH 2 ) n L and wherein n is equal to one, R 3 is H and L is equal to a heteroaryl selected from thiophene or pyridyl or furan or substituted versions thereof wherein the substituents are selected from typical aromatic substituents (e.g.
  • n is equal to two and wherein the heteroaryl group is attached to the 2-ethyl carbon include members selected from
  • the present invention also relates advantageously to a compound of formula B wherein n is equal to two, R 3 is H and L is equal to W wherein W is selected from the group consisting of:
  • these groups may be selected from -OPh, halo, -CH 2 -COOR' or -CH 2 CONR'R", -OCH 2 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OCH 2 CH 3 , -O-2-methoxyphenyl, -S(O) 2 Ph, -S(O) 2 NR'R", -CF(CF 3 ) 2 , -CF 2 CF 3 ,
  • the present invention also relates to pharmaceutical compositions containing a preferred compound of formula B as shown above and a pharmaceutically acceptable carrier.
  • Scheme 8 shows that some of the compounds disclosed herein can exist and be drawn in various true tautomeric forms (i.e., imine to enamine conversion in the B ring).
  • certain compounds of formula B may contain an asymmetrically substituted carbon atom, and accordingly may exist in, and be isolated in, optically-active and racemic forms.
  • certain compounds of formula B for example, those containing a double bond, may exist in, and be isolated in, separate stereoisomeric forms ('E' and 'Z') about that group. Some compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically-active, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the treatment of neurodegenerative disorders, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form or by synthesis from optically-active starting materials) and individual 'E' and 'Z' stereoisomers (for example, by chromatographic separation of a mixture thereof) and how to determine neuroprotective properties by the standard tests described hereinafter.
  • the invention further provides a method for the treatment of neurological disorders, comprising administering to a mammal in need of such treatment an effective amount of a compound according to the invention as defined above, or a pharmaceutically acceptable salt thereof, or a composition as defined above.
  • the invention also encompasses a method of antagonizing an NMDA receptor in mammals comprising administering a pharmaceutically effective amount of the compound or its salt as claimed herein or a pharmaceutical composition as recited herein to a patient in need of treatment thereof.
  • the preferred therapeutic treatment area is prevention and/or treatment of stroke.
  • a pharmaceutically effective amount of a compound as claimed and disclosed in the present invention may be administered immediately after an ischemic event to prevent cell damage and/or cell death.
  • the present invention is also directed to a method of preventing and/or treating damage induced by the excitatory amino acids such as
  • the invention also relates to a method of preventing the excessive influx of calcium ions in central neurons.
  • the invention relates to a method of preventing ischemic neuronal injury following transient global ischemia and a method of reducing infarct volume following focal ischemic insults by treating a patient in need of treatment thereof with a pharmaceutically effective amount of a compound of formula A or B wherein ring A and R 1 and R 2 are as defined herein.
  • the compounds and compositions of the invention may be extremely beneficial in preventing neurological morbidity during cardiac resuscitation or administered as cerebral prophylatics during high-risk surgery.
  • alkyl and alkoxy include both straight and branched chain radicals, but it is to be understood that references to individual radicals such as “propyl” or “propoxy” embrace only the straight chain (“normal") radical, branched chain isomers such as “isopropyl” or “isopropoxy” being referred to specifically.
  • halo is inclusive of fluoro, chloro, bromo, and iodo unless noted otherwise.
  • heteroaryl includes those heteroaromatic groups of benz derivatives thereof where are specifically or generally described or disclosed in this specification.
  • (1-4C)alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • (2-4C)alkyl containing a double or triple bond examples include vinyl, 2-propenyl (i.e. allyl), 2-propynyl, (i.e. propargyl), 2-butenyl, and 3-butenyl.
  • (1-4C)alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and t-butoxy.
  • Particular values of (1-12C)alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, text-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, 2,2,4-trimethylpentyl, nonyl, isononyl, decyl, isodecyl, undecyl, isoundecyl, dodecyl and isododecyl.
  • Particular values of (1-12C)alkyl containing a double or triple bond include vinyl, 2-propenyl(i.e. allyl), 2-propynyl(i.e. propargyl), but-2-enyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
  • (1-6C)alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
  • (2-6C)alkyl containing a double or triple bond examples include vinyl, 2-propenyl (i.e. allyl), 2-propynyl, (i.e. propargyl), but-2-enyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
  • Particular values of phenyl substituted with from 0-4 substituents may include but are not limited to phenyl; 2-, 3-, and 4-halophenyl; 2-, 3-, and 4-aminophenyl; 2-, 3-, and 4-hydroxyphenyl; 2-, 3-, and 4-cyanophenyl; 2-, 3-, and 4-nitrophenyl; 2-, 3-, and 4-methylphenyl; 2-, 3-, and 4-ethylphenyl; 2-, 3-, and 4-propylphenyl; 2,3 or 4-isopropylphenyl; 2-, 3-, and 4-methoxyphenyl; 2-, 3-, and 4-ethoxyphenyl; 2-, 3-, and 4-propoxyphenyl; and 3,5-dihalophenyl, 3-halo-4-hydroxyphenyl, and 3, 5-dihalo-4-hydroxyphenyl and phenyl substituted at 1, 2 or 3 carbon atoms with methoxyethyloxy,
  • 2,4-dihalophenyl, 4(tetrazole)phenyl 3,5-trifluoromethylphenyl, 2,4-dimethylphenyl, 3-halo-4-methylphenyl, 4-trifluoromethylphenyl, 3,4-dimethylphenyl, 2-methyl-4-methoxyphenyl, 2-methoxy-4-halophenyl, 2-methyl-4-hydroxyphenyl, 2,3-dimethylphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,5-dimethylphenyl, 4 (benyloxy)phenyl,
  • Particular values of phenyl (1-4C)alkyl substituted with from 0-4 substituents may include benzyl, phenylethyl, phenylpropyl, phenylbutyl; 2-, 3-, 4 and 5-halobenzyl; 2-, 3- and 4- CF 3 -benzyl, 2-, 3-, and 4-aminobenzyl; 2-, 3-, and 4-cyanobenzyl, 2-, 3-, and
  • methoxyethyloxy methoxyethyloxyethyloxy, N,N-dimethylethyloxy, and N,N-dimethylethylaminyl; 3,4-dimethoxy; 3,4-dihydroxy; 3,5-dimethoxy; 3,5-dihydroxy or 2,3,4-SMe or 2,3,4-SH.
  • Particular values of 4- to 7-membered rings containing nitrogen may include piperidino, pyrrolidinyl, and azetidinyl.
  • heterocyclic species with 2 heteroatoms include piperazinyl, morpholinyl, oxazolinyl or thiazinyl.
  • heterocycles or substituted derivatives thereof include
  • halo include chloro and bromo.
  • (1-3C)perfluoroalkyl include trifluoromethyl and pentafluoroethyl.
  • More particular values of 4- to 7-membered rings containing nitrogen include piperidino, piperazinyl and pyrrolidinyl.
  • heteroaryl More particular values of heteroaryl include tetrazole, furan thiophene, diazole, imidazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine.
  • m More particular values include 0-2.
  • n More particular values of n include 0-2.
  • phenyl substituted with from 0-3 substituents may include phenyl; 2- and 4-halophenyl; 2- and
  • phenyl (C1-C4)alkyl substituted with 0-3 substituents may include benzyl; phenylethyl; 2- and
  • R 1 examples include hydrogen, hydroxyethyl, (methoxyaniline)ethyl, phenoxyphenyl, alkoxyhalophenyl,
  • R 1 More preferred values of R 1 include 2-hydroxyethyl, 2- (4'methoxyaniline)ethyl,phenyl,4-methoxyphenyl, 2-methyl-4-bromophenyl, benzyl, 4-fluorophenyl, 4-methylphenyl,
  • R 3 include hydrogen and (COR 6 ). More preferred values for R 3 are hydrogen.
  • R 5 examples include H, C1-4alkyl or benzyl.
  • R 5 More preferred values for R 5 are H.
  • R 6 examples include C1-12alkyl or phenyl.
  • R 6 More preferred values for R 6 are hydrogen.
  • Preferred values for R 6 include those groups designated as particular values for (1-12C)alkyl or for (1-12C)alkyl containing a double or triple bond or substituted versions thereof and also include phenyl and substituted version thereof. More preferred values include hydrogen, methyl, phenethyl, phenyl, isobutyl, tert-butyl, isopropyl, ethyl, or benzyl.
  • R 4 examples include hydrogen, fluoro, chloro, bromo, iodo, amino, methyl, ethyl, propyl, allyl, propargyl,
  • R 4 More preferred values of R 4 include hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, trifluoromethyl, nitro, methoxy, amino, and cyano.
  • Preferred compounds having formula B include:
  • Pyridazinediones of formula A or B can be made by processes which include processes known in the chemical arts for the production of structurally analogous compounds.
  • the preparation of compounds wherein Z is H on certain starting materials described herein can be affected by chlorinating the hydroxy group of the dialkyl 4-OH quinoline-2,3-dicarboxylate (starting material) using phosphorous oxychloride. This chlorine is then reduced using tetrakistriphenylphosphine Pd(O) and sodium formate to provide dimethyl quinoline-2,3-dicarboxylate which is then processed through the remaining chemical steps (e.g.
  • heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole, oxadiazole wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic
  • substituents include typical aromatic substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to -(CH 2 ) n via a carbon atom on the heteroaryl group; which forms a compound of formula V ( a pyrrolo[3,4-b]quinoline) by refluxing the above reactants in (1) ethanol or other suitable solvent for a 12 hour period followed by reflux in acetic acid (AcOH).
  • the compound of formula V is then treated with methanesulfonic acid (MeSO 3 H) in refluxing methanol or other suitable solvent for an eighteen hour period to form a compound of formula I wherein R 1 or R 2 is aryl as defined above (Scheme 1);
  • R 1 or R 2 is a substituted alkyl species as described above.
  • the resulting compounds (when Y is OH, SH or NHR) can then be further derivatized to form compounds wherein W is NR'COR", OCONR', NR'CO 2 R",
  • the isomeric mixture is treated with aqueous meglumine or aqueous meglumine/choline mixture to form a solution which is further acidfied with acetic acid to pH 6-7.
  • the solid precipitate is then filtered off to separate the 3-positional isomer while the filtrate is then further treated with acetic acid to a pH of around 5.5 to form a solid which is the 2-positional isomer (VI').
  • R 2 is -(CH 2 ) n Heterocycle wherein heterocycle comprises a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2 or 3 heteroatoms chosen from O, N, or S wherein an N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heterocycle may be substituted with R or R' or to form a compound of formula I with R 1 as -(CH 2 ) n Nu wherein Nu is also equal to
  • the solvents used in the formation of the hydrazide include any anhydrous organic solvent selected from, for example THF, toluene CH 2 Cl 2 , CH 3 Cl hexane or any inert organic solvent.
  • the present invention relates to a novel process for producing the 2-substituted pyridazino quinolines of formula I (or II) wherein R 1 is aryl or heteroaryl comprising the steps of (i) forming the 3-carboalkoxy-2-acid halide intermediate from the corresponding dialkyl ester of formula IV and (ii) reacting said halide from step (i) with either an arylhydrazine wherein aryl is as defined above under the conditions described in the examples or an heteroarylhydrazine wherein heteroaryl is as defined above under the conditions described in the examples to form a compound of formula II wherein R 1 is aryl or heteroaryl.
  • Variable amounts of the 3-isomer is also produced in this process.
  • R 1 is aryl.
  • the hydrazide may, depending upon the aryl or heteroaryl substituents, proceed directly to the 2-substituted PQD or via the 5-membered pyrrole intermediate which then forms both the 2 and 3 substituted PQD. Electron donating groups on the aryl ring promote selective formation of the 2-substituted PQD. Steric effects may also influence the degree of selectivity.
  • t-butylO(CO)-N-N-R include any alkylaryl, aryloxyalkyl,
  • alkyloxyalkyl, alkyloxyalkyloxy or alkylheteroaryl recited herein wherein the alkyl group has a suitable leaving group (b) a suitable aryl or substituted aryl hydrazine with di-t-butyl-dicarbonate in an organic solvent (e.g. THF or equivalent) or (c) (for n 1-4) a suitable aryl or substituted aryl aldehyde or substitutes alkylaldehyde with t-butylcarbazate in refluxing hexanes or equivalent organic solvent to form the corresponding imine which is then reduced with a reducing agent (e.g.
  • R 1 -substituted t-butyl carbonate hydrazines are readily prepared.
  • N-2 aryl and heteroaryl substituted isomers may readily and selectively be prepared as shown in Scheme 7 by treating an aryl or heteroaryl hydrazine with benzaldehyde followed by a reduction of the hydrazide imine to form an N-aryl-N-benzyl substituted hydrazine. This compound is then reacted with a 3-carboxyester-2-acid halide quinoline to form a hydrazide intermediate, e.g.
  • a compound of formula I wherein L is a heterocyclic moiety such as a 4-(C1-C6) substituted piperazine or 4-arylsubstituted piperazine or a phthalimido or another commercially available nucleophilic heterocycle may be formed by reacting the heterocyclic nucleophilic species with a 2- or 3- halo(C1-C6alkyl)pyridazino[4,5-b]quinolines of formula I, the latter of which is prepared from the corresponding hydroxy species as described in (d) above.
  • a heterocyclic moiety such as a 4-(C1-C6) substituted piperazine or 4-arylsubstituted piperazine or a phthalimido or another commercially available nucleophilic heterocycle
  • G, H, i, J, K, L, M, N, O, P and D'-P' are prepared via the analogous processes described in steps (a) -(g).
  • Formulae shown generally as Q, Q', R, R', S or S' show various acylated intermediates or glycine receptor antagonists which are prepared from the corresponding non-acylated species.
  • acylation of a compound of formula I or II, including those species wherein R 1 and R 2 equal H may be achieved before reduction of the B-ring carbonyl or enamine under the general conditions specified herein.
  • a compound of formula Q-S' is formed wherein the compounds are useful as intermediates whether or not they are also active as glycine receptor antagonists.
  • the single dashed line indicates a double bond may be present depending upon the valency or groups attached to the C-1 or C-4 position of the PQD ring structure.
  • Formulae shown as Q, Q', R, R', S and S' indicate the possible formulae which form the basis for A or A' as indicated. For example,
  • (C1-6)alkyl or (C1-6)alkylaryl may be prepared from the corresponding compound of formula I or II by alkyl or alkylaryl addition to the
  • T wherein the B ring double bond is present and the B-ring carbonyl is present may be prepared by acylating a compound of formula II to form
  • a compound of formula T' is useful as an intermediate to produce compounds of formula A or A' and is useful as a glycine receptor antagonist and is claimed herein.
  • a compound of formula T may also be formed by reducing a compound of formula IV so that the ketone remains intact and the double bond of the enamine is reduced. This product may be formed in a reduction of IV which may be carried forward via coupling and cyclization to a PQD of formula T.
  • Scheme 8 describes how some of the compounds within the scope of the present invention are prepared. The preferred compounds are those of formula B.
  • the preferred process for producing compounds of formula B involves (i) preparing a starting PQD of formula II and reducing this compound under the appropriate conditions to a compound of formula B.
  • the preferred conditions involve suspending a compounding of formula II (specifically prepared as shown in examples 1-144) in an organic solvent selected from, but not limited to, THF with subsequent addition of trifluoroacetic acid (significant molar excess). This suspension is cooled to about 0°C and sodium borohydride is added in molar excess (5X). The reduction is then allowed to proceed at 0°C for about 15 minutes and then warmed to room temperature and stirred for about 3 hours. Upon work-up and after triturating and filtering (2X), the title compounds are readily obtained.
  • Z on a compound of formula II is oxygen.
  • Z, in a compound of formula I' may also be hydrogen, OH SH or NHR.
  • N-2 hydroxy alkyl PQD which is further reacted with lower alkyl (C1-4)-acids to form the corresponding ester.
  • the carbon chain bonded to the N-2 nitrogen may vary from 1-6 carbon atoms with the hydroxy group on the terminal position.
  • N-2 aryl derivatives are also prepared in examples 35 etc. wherein a key intermediate is the quinoline 2-acid chloride which is reacted with an aryl hydrazine to form, in some cases selectively, the N-2 aryl PQD.
  • N-methyl-glucamine or other salts e.g. choline, sodium etc.
  • the intermediate generated from the acid chloride is the 3-carboalkoxy-4-hydroxyquinoline
  • 3-carboalkoxyquinoline2-carboxylic acid N-2 substituted hydrazide Improved conditions using 1 eq of the starting aryl hydrazine are described in the examples.
  • methanesulfonic acid in methanol or THF has been utilized to cyclize the intermediate hydrazide.
  • any methoxyphenyl species may be hydrolyzed with HBr or other acid (e.g. CH 3 SO 3 H) to form the corresponding hydroxy species.
  • N-2 hydroxy alkyl PQD compounds are utilized to form the corresponding N-2 haloalkyl PQD derivatives which are used as intermediates to form, for example, the N-2 alkyl (C1-C4)thio
  • alkyl (C1-C4) compounds The appropriate thiolate anion in DMF is reacted with an N-2 haloalkyl PQD.
  • N-2 haloalkyl PQD N-2 haloalkyl PQD
  • amines, anilines or other heterocyclic or heteroaryl nucleophiles may react with the N-2-alkyl(C1-C4)halo PQD to form the corresponding-nucleophilic substituted PQD.
  • DMF or equivalent organic solvent is utilized in this process.
  • a key process for selectively producing N-2 aryl, heteroaryl, substituted alkyl or other species prepared from any N-2 intermediates involves the initial production of a 2-pyrrolidinoamido substituted quinoline which is formed from the corresponding 2-carboxy 3-carboalkoxy quinoline.
  • This compound or analogous compounds e.g. with groups equivalent to pyrrolidinoamido is hydrolyzed to form the
  • intermediate - e.g. 2-pyrrolidinoamido-3-carboxylic acid-NR -N(BOC) hydrazide which, under the cyclization conditions, forms the N-2 substituted PQD without any N-3 substituted PQD formed. While this process is primarily utilized to form the immediate precursors to the reduced PQDs (e.g. compounds of the invention), it may also be utilized using or via intermediates G, G', H, H', P or P'.
  • hydrazines utilized in this process are readily prepared from, commercially available materials as described herein wherein either t-butylcarbazate or di-t-butyldicarbonate are utilized to BOC one N of the hydrazine depending upon whether R 1 is aryl or alkylaryl or alkyl or substituted alkyl or heteroaryl or alkyl heteroaryl.
  • R 1 is aryl or alkylaryl or alkyl or substituted alkyl or heteroaryl or alkyl heteroaryl.
  • the benzyl or substituted benzyl compounds described herein are readily and conveniently prepared from the appropriate
  • Another intermediate and glycine receptor antagonist includes N-2-aryl PQDs of formula B substituted with a cyano
  • heterocyclic compounds or benz or heteroaryl benz derivatives thereof which are glycine receptor antagonists An N-2 halo(C1-4) alkyl PQD is reacted with the selected nucleophile (heterocyclic or heteroaryl wherein heteroaryl includes for example, those compounds shown in the examples and described herein) to form the corresponding N-2
  • N-2 heterocyclic PQDs can be further hydrolyzed to form amido alcohols within the scope of the present invention.
  • oxizolidine diones are readily hydrolyzed to the
  • the necessary starting materials for the procedures such as that described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples.
  • Certain diesters of formula IV for use in reacting with substituted hydrazine to make a compound of formula I can be made by treating a compound of formula VII with a suitable base, such as an alkali metal alkoxide (e.g., potassium t-butoxide) in a suitable solvent such as t-butanol to effect ring closure and thereby yield the desired diester.
  • a suitable base such as an alkali metal alkoxide (e.g., potassium t-butoxide) in a suitable solvent such as t-butanol
  • R 15 is (C1-C3)alkyl if a value for Z of hydroxy (or the tautomerically equivalent oxo) is desired; (It is noted that higher alkyl esters can be employed, but they do not provide any synthetic advantage.)
  • IV can be made in a one-pot process without separating the compound of formula VII from the reaction mixture.
  • a diester of formula IV wherein Z is hydroxy (or oxo) can also be made by treating an isatoic anhydride of formula X directly with a sodium or potassium salt of a (C1-C3)dialkyl (e.g. diethyl) ester of 2-oxosuccinic acid in a suitable solvent such as
  • a diester of formula IV wherein Z is thiohydroxy can be made by treating a corresponding diester of formula IV wherein R 3 is hydroxy with Lawesson's reagent, 2,4-bis(4-methoxyphenyl)-1,3-dithia- 2,4-diphosphetane-2,4-disulfide, in a suitable solvent such as toluene or dimethoxyethane and at a temperature in the range of 50-110 °C.
  • a substituted imide of formula V wherein the B-ring N loses its H and Z is, for example, NH 2 can be made by treating a diester of formula IV, wherein the value corresponding to Z is a halo group such as chloro or bromo, with ammonia which forms the corresponding phthalimide which is then further reacted with arylhydrazine to form
  • a compound of formula VII, wherein Y is CN, CHO, COOR 15 , CSOR 15 , or CSSR 15 wherein R 15 is a C1-C10 alkyl, alkenyl or alkynyl group can be made by treating a corresponding ortho amine of formula VIII with a dialkyl acetylenedicarboxylate, such as dimethyl
  • acetylenedicarboxylate in a suitable solvent such as a
  • An ortho amine of formula VIII' can be made by esterifying a corresponding acid of formula VIII' by conventional methods.
  • An acid of formula VIII' can in turn be made by deprotecting a corresponding compound of formula VIII" wherein the amino group has been protected with a conventional protecting group Pr (such as tert-butoxycarbonyl, t-BOC).
  • Pr such as tert-butoxycarbonyl, t-BOC.
  • a compound of formula VIII" can in turn be made by
  • an organolithium compound for example t-butyllithium
  • a dilithiated species which can be carboxylated by reacting with carbon dioxide.
  • An amine of formula IX can be prepared by protecting a corresponding (unprotected) amine by conventional methods.
  • esterification step is effected by using a base (for example, sodium hydride) followed by an alkylating agentR 15 X on the protected acid of formula VIII" rather than on the acid of formula VIII'.
  • a base for example, sodium hydride
  • An ortho amine of formula VIII', wherein Y is COOR 15 can also be made by treating a corresponding isatoic anhydride of formula X with base (such as an alkali metal hydroxide) in alcoholic solvent of formula R 15 OH.
  • base such as an alkali metal hydroxide
  • An isatoic anhydride of formula X can be made by treating an isatin of formula XI with chromium trioxide in the presence of acetic anhydride, or with a peroxycarboxylic acid such as the "magnesium salt of monoperoxyphthalic acid, and in a suitable solvent such as acetic acid.
  • An isatin of formula XI can be made by cyclizing a
  • a hydroxyimino acetamide of formula XII can be made by treating an amine of formula XIII with chloral hydrate in the presence of sodium sulfate and hydroxylamine hydrochloride and in a suitable solvent such as water.
  • the N-t-butoxy carbonyl hydrazines utilized in the present invention may be prepared according to the procedure set forth in Example 82C.
  • N-t-butoxy carbonyl-N'-pentafluorobenzylhydrazine N-t-butoxy carbonyl-N' -2-cyanobenzylhydrazine; N-t-butoxy carbonyl-N'-3-chlorobenzyl hydrazine; N-t-butoxy carbonyl-N'-3,5-ditrifluoromethyl benzyl hydrazine; N-t-butoxy carbonyl-N'-3-phenylpropylhydrazine; N-t-butoxycarbonyl-N'-4-methylbenzyl hydrazine; N-t-butoxy carbonyl-N'-4-trifluoromethylbenzyl hydrazine; N-t-butoxy carbonyl-N'-4-cyanobenzyl hydrazine; and
  • N-t-butoxy carbonyl-N' -2 4-dimethylphenyl hydrazine The present invention, therefore, also relates to these novel hydrazine moieties and to processes for their production and use as intermediates to couple with the key intermediate 2-pyrolidinocarbamide quinoline 3-carboxylic acid to form a compound of formula B via a novel and inventive process as described herein which selectively forms the N-2-substituted PQD.
  • the intermediate hydrazines utilized to prepare N-2-aryl or N-2-substituted aryl PQDs may also be prepared according to the non-limiting example 42a.
  • N'-t-butoxy carbonyl-N' -aryl or substituted aryl compounds are produced via this novel process to enable selective formation of the N-2-substituted PQDs.
  • This process may be the preferred route to aryl substituted compounds claimed and recited herein. Intermediates or compounds shown as D-P or D'-P' are part of the present invention.
  • Process steps recited as (j)-(r) describe alternative methods which may be utilized to prepare the compounds claimed herein.
  • the preferred route involves preparing a starting material as described in process steps (a)-(i) and then reducing this compound of formula II to a compound of formula B. It is noted that many of the starting materials for synthetic methods as described above are commercially available and/or widely reported in the scientific literature.
  • Suitable pharmaceutically acceptable salts are salts formed with bases which form a physiologically acceptable cation, such as alkali metal (especially lithium, sodium and
  • alkaline earth metal especially calcium and magnesium
  • aluminum and ammonium salts as well as salts made with appropriate organic bases such as choline hydroxide, triethylamine, morpholine, piperidine, ethylenediamine, lysine, ethanolamine, diethanolamine, triethanolamine, N-methyl-D-glucamine (meglumine), arginine, and tris(hydroxymethyl)aminomethane.
  • Choline, meglumine, sodium and potassium salts are preferred. Choline, sodium and potassium salts are especially preferred.
  • a pyridazinedione of formula B When used to intervene therapeutically following a stroke, a pyridazinedione of formula B generally is administered as an appropriate pharmaceutical composition which comprises a compound according to the invention as defined hereinbefore together with a pharmaceutically acceptable diluent or carrier, the composition being adapted for the particular route of administration chosen.
  • Such compositions are provided as a further feature of the invention. They may be obtained employing conventional procedures and excipients and binders and may be in a variety of dosage forms. For example, they may be in the form of tablets, capsules, solutions or suspensions for oral administration; in the form of suppositories for rectal
  • a compound of according to the invention will necessarily be varied according to principles well known in the art taking account of the route of administration, the severity of the postischemic disorder, and the size and age of the patient.
  • a compound of according to the invention will be administered to a warm blooded animal (such as man) so that an effective dose is received, generally a dose in the range of about 0.01 to about 100 mg/kg body weight.
  • a warm blooded animal such as man
  • an effective dose is received, generally a dose in the range of about 0.01 to about 100 mg/kg body weight.
  • the compound is administered intravenously, it is administered in the range of about 0.01 to about 10 mg/kg body weight.
  • it is administered orally, it is administered in the range of about 0.5 to about 100 mg/kg body weight.
  • a compound according to the invention can be co-administered with other therapeutic or prophylactic agents and/or medicaments that are not medically incompatible therewith.
  • representative compounds of the instant invention do not show any indication of overt toxicity in laboratory test animals.
  • the actions of compounds according to the invention as antagonists at the glycine receptor of the NMDA receptor complex can be shown by one or more standard tests such as the [ 3 H]-glycine binding assay (Test A) and by tests in vivo such as the red nucleus test (Test B) and the Rat Middle Cerebral Artery test (Test C). These tests confirm that compounds of the invention are NMDA receptor antagonists in vitro and in vivo. Certain compounds of the invention are highly potent NMDA receptor antagonists. In particular, the compounds of the present invention of formula A with R 1 as an alkyl, aryl or heterocycle or heteroaryl as defined herein and R 2 as H are highly potent NMDA receptor (Glycine) antagonists.
  • neuronal synaptic membranes are prepared from adult (about 250 g) male Sprague-Dawley rats. Freshly dissected cortices and hippocampi are homogenized in 0.32 M sucrose (110 mg/mL). Synaptosomes are isolated by
  • the supernatant is pelleted (20,000 xg, 20 min) and resuspended in double-distilled water.
  • the suspension was centrifuged for 20 minutes at 8,000 xg.
  • the resulting supernatant and buffy coat are washed twice (48,000 xg, 10 mins, resuspension in double-deionized water).
  • the final pellet is quickly frozen (dry ice/ethanol bath) under double-deionized water and stored at -70 °C.
  • [ 3 H]-glycine binding at the N-methyl-D-aspartate receptor 20 nanomolar [ 3 H]-glycine (40-60 Ci/mmol, New England Nuclear, Boston, MA) is incubated with the membranes suspended in 50 millimolar tris (hydroxymethyl)aminomethane citrate, pH 7.1 for 30 minutes at 4 °C. Glycine, 1 millimolar, is used to define the nonspecific binding. Bound [ 3 H]-glycine is isolated from free using a Brandel (Biomedical Research and Development Laboratories,
  • the other designated examples disclosed herein are glycine antagonists within the scope of the present invention.
  • Examples 1-144 are simply described as starting materials and do not fall within the scope of the present invention.
  • the present invention does however, include all the reduced species of examples 1-144 which may fall within formula A or A' or B or B', or T' and other intermediates as designated herein..
  • HA-966 racemic
  • CGP 37849 are reference agents that have been shown active in this test (ID50s of 7.9 and 1.7 mg/kg iv, respectively).
  • the procedure for the red nucleus test is as follows. Rats are anesthetized with chloral hydrate (400 mg/kg ip) and the femoral vein is catheterized for iv drug administration. Five-barrel micropipettes are stereotaxically positioned in the red nucleus. Typically, three to four of the five barrels are filled as follows: the recording barrel with 2M potassium citrate, the current balancing barrel with 4M NaCl, the drug barrel with 25mM NMDA, and another drug barrel with 2.5mM quisqualic acid (QA is only used in selectivity studies). NMDA is iontophoretically applied with an ejection current that is adjusted depending on the sensitivity of each individual red nucleus cell.
  • the NMDA is cycled on and off (usually 30 - 60 sec. on and 60 - 120 sec. off) and the firing rate of the cell during each period is recorded. Once the baseline firing rate of the cell has been established, the test drug is administered iv. The effect of the drug on the
  • NMDA-induced excitatory response of the red nucleus cell can be both qualitatively and quantitatively evaluated from the recordings and the raw data accumulated.
  • Compounds of the invention exhibited a significant antagonist response.
  • MCA middle cerebral artery
  • necrotic tissue is readily distinguished from the intact brain and the area of infarcted cortex can be traced on an image analyzer.
  • the infarct volume for each section is quantified with an image analyzer, and the total infarct volume is calculated with a program that summed all interval volume. See S. Brint et al. J.
  • Kieselgel (Art 9385) and column chromatography on Merck Kieselgel 60 (Art 7734); [these materials were obtained from E. Merck, Darmstadt, W. Germany]; thin layer chromatography (TLC) was carried out on Analtech 0.25 mm silica gel GHLF plates (Art 21521), obtainable from Analtech, Newark, DE, USA;
  • melting points are uncorrected and (d) indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations;
  • Examples 1-144 are described to show how to prepare an immediate precursor utilized in the reduction of compounds of compounds of formula I, I", II or III to a compound of formula A, A', B, B', C or C'.
  • Example 145 describes the experimental procedure utilized to reduce a compound of formula. I to a compound of formula A (or II to B).
  • Examples 146 - 177 are shown in Table 9 and these examples were prepared as described in Example 145. As the examples and in vitro or in vivo results indicate, the present invention or the compounds and glycine receptor
  • antagonists recited herein are useful as in vitro tools for determining relative glycine antagonist properties and as in vivo compounds or compositions which are useful as in vivo tools for determining relative antagonist properties and as compounds or compositions which antagonize the glycine receptor in animals or humans in need of treatment thereof.
  • present invention e.g. A, A', B, B'... or T'or U
  • invention therefore, also relates to a method of in vitro antagonism of a mammalian glycine receptor comprising administering an antagonist effective amount of a compound of formula A or A' or B or B' or T' wherein the respective variables (R 1 - R 6 ) are as recited previously.
  • the invention further relates to a method of in vivo antagonism of a mammalian, including human, glycine receptor comprising administering a pharmacologically effective amount of a compound of formula A or A', B or B' or T' to a mammal or a human wherein the variables for A, A', B, B' or T' are as previously defined.
  • the starting dimethyl 7-chloro-4-hydroxyquinoline-2,3-diccarboxylate was prepared as follows: a. dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate.
  • the starting 2(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione was prepared as follows: a. 2(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione.
  • 6-Chloro-2-anilino-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]- quinoline-1,3,9-trione (1.70 g, 5.00 mM) was stirred in methanol (0.85 L), and methanesulfonic acid (85 mL) was added. The yellow suspension was heated to reflux for 16 hours and cooled to room temperature.
  • 6-Chloro-2-anilino-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione was prepared in the following manner: a. 6-Chloro-2-anilino-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]-quinoline-1,3,9-trione.
  • a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.50 g, 8.45 mM) in ethanol (35 mL) was added phenyl hydrazine (5.82 mL, 59.20 mM) to give a brown solution.
  • Example 7 7-Chloro-1-hydroxy-3-(4-methoxyphenyl)-3,4,5,10-tetrahydropyridazino[4,5-b]quinoline-4,10-dione.
  • 6-Chloro-2-(4-methoxyanilino)-2,3,4,9-tetrahydro-1H- pyrrolo[3,4-b]-quinoline-1,3,9-trione (2.72 g, 7.40 mM) was stirred in methanol (200 mL), and methanesulfonic acid (50 mL) was added. The tan suspension was heated to reflux for 16 hours during which it turned yellow. This yellow suspension was cooled to room temperature and filtered (the filtrate was saved for use in Example 8).
  • Triethylamine (1.88 mL, 13.52 mM) was added, and the mixture was heated to reflux for 40 hours. The resulting suspension was filtered hot, and the collected solids were washed with ethanol to give the 4-methoxyphenyl hydrazine salt of the title compound (0.700 g) as a light tan solid. This material was heated to reflux in glacial acetic acid (20 mL) for 2 hours to give a brown suspension. The suspension was cooled to room temperature.
  • Example 7 The saved filtrate from Example 7 was diluted with water (250 mL) to give a yellow suspension. The solids were collected and washed with aqueous methanol (50%) to give the title compound (1.22 g, 45%) as a dull yellow powder, mp 351-353°C; MS(CI): 370 (M+H).
  • the starting 2-anilino-7-nitro-2,3,4,9-tetrahydro-1H-pyrrolo- [3,4-b]quinoline-1,3,9-trione was prepared in the following manner: a. 2-Anilino-7-nitro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]-quinoline-1,3,9-trione.
  • Example 16 7-Chloro-1-hydroxy-3-(4-chlorophenyl)-3,4,5,10-tetrahydropyridazino[4,5-b]quinoline-4,10-dione.
  • 6-chloro-2-(4-chloroanilino)-2,3,4,9-tetrahydro-1H-pyrrolo-[3,4-b]quinoline-1,3,9-trione was prepared as follows: a. 6-chloro-2-(4-chloroanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione.
  • Example 17 7-Chloro-4-hydroxy-2(4-chlorophenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione.
  • Example 16 The filtrate saved from Example 16 was diluted with water (75 mL) to give a white suspension which was stirred for 16 hours. This suspension was filtered, and the collected solids were washed successively with water, aqueous methanol, methanol/ether and ether to give the title compound (0.420 g, 63%) as a white powder, mp 359-36°C; MS(CI): 374 (M+H).
  • the starting 6-chloro-2-(4-methylanilino)-2,3,4,9-tetrahydro-1H-pyrrolo-[3,4-b]quinoline-1,3,9-trione was prepared in the following manner: a. 6-chloro-2-(4-methylanilino)-2,3,4,9-tetrahydro-1H-pyrrolol3,4-b]quinoline-1,3,9-trione.
  • Example 20 7-Chloro-1-hydroxy-3-(4-isopropylphenyl)-3,4,5,10- tetrahydropyridazino[4,5-b]-quinoline-4,10-dione.
  • the starting 6-chloro-2-(4-isopropylanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione was prepared in the following manner: a. 6-chloro-2-(4-isopropylanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]-quinoline-1,3,9-trione.
  • Example 21 7-Chloro-4-hydroxy-2-(4-isopropylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]-quinoline-1,10-dione.
  • Example 22 7,9-Dichloro-1-hydroxy-2-phenyl-1,2,5,10-tetrahydro ⁇ pyridazino [4,5-b]-quinoline-1,10-dione.
  • the starting 6,8-dichloro-2-anilino-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]-quinoline-1,3,9-trione was prepared in the following manner: a. 6,8-Dichloro-2-anilino-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]-quinoline-1,3,9-trione.
  • Example 23 7-Chloro-1-hydroxy-3-(1-naphthyl)-3,4,5,10-tetrahydro ⁇ pyridazino[4,5-b]quinoline-4,10-dione.
  • 6-Chloro-2-(1-naphthylamino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.30 g, 3.34 mM) was stirred in methanol (0.65 L) and methanesulfonic acid (65 mL) was added. The brown suspension was heated to reflux for 16 hours during which the solids dissolved to give a brown solution. This solution was cooled to room temperature. Addition of ice (10 mL) gave a tan suspension which was stirred for 1.5 hours.
  • 6-chloro-2-(1-naphthylamino)-2,3,4,9-tetrahydro -1H-pyrrolo-[3,4-b]quinoline-1,3,9-trione was prepared as follows: a. 6-chloro-2-(1-naphthylamino)-2,3,4,9-tetrahydro-1H-pyrrolo [3,4-b]quino-line-1,3,9-trione.
  • Example 24 7-Chloro-4-hydroxy-2-(1-naphthyl)-1,2,5,10-tetrahydro-pyridazino[4,5-b]quinoline-1,10-dione.
  • the filtrate saved from Example 23 was diluted with water (0.75 L) and then partially concentrated on a rotary evaporator to give a brown suspension.
  • the solids from the suspension were collected and washed with water, methanol/ether and ether to give a brown powder (0.535 g).
  • This material was heated to reflux in methanol (23 mL) and filtered hot to remove undissolved solids which were discarded.
  • the filtrate was concentrated to dryness and triturated with ethyl acetate (20 mL) .
  • Example 25 7-Chloro-3-(4-fluorophenyl)-1-hydroxy-3,4,5,10-tetrahydropyridazino[4,5-b]quin-oline-4,10-dione.
  • the starting 6-chloro-2-(4-fluoroanilino)-2,3,4,9-tetrahydro- 1H-pyrrolo-[3,4-b]quinoline-1,3,9-trione was prepared in the following manner: a. 6-chloro-2-(4-fluoroanilino)-2,3,4,9-tetrahydro-1H-pyrrolo [3,4-b]quinoline-1,3,9-trione.
  • Example 26 7-Chloro-2-(4-fluorophenyl)-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quin-oline-1,10-dione.
  • Example 27 3-(4-Bromophenyl)-7-chloro-1-hydroxy-3,4,5,10-tetrahydropyridazino[4,5-b]quino-line-4,10-dione.
  • the starting 2-(4-bromoanilino)-6-chloro-2,3,4,9-tetrahydro -1H-pyrrolo-[3,4-b]quinoline-1,3,9-trione was prepared in the following manner: a. 2-(4-Bromoanilino)-6-chloro-2,3,4,9-tetrahydro- 1H-pyrrolo.3,4-b]quinoline-1,3,9-trione.
  • Example 28 2-(4-Bromophenyl)-7-chloro-4-hydroxy-1,2,5,10-tetra-hydropyridazino[4,5-b]quino-line-1,10-dione.
  • the filtrate saved from Example 27 was diluted with water (550 mL) to give a tan suspension which was stirred for 2 hours. The suspension was filtered and washed successively with water,
  • Example 29 7-Chloro-1-hydroxy-3-(2-methoxyphenyl)-3,4,5,10-tetrahydropyridazino[4,5-b]quin-oline-4,10-dione.
  • the starting 6-chloro-2-(2-methoxyanilino)-2,3,4,9-tetrahydro- 1H-pyrrolo-[3,4-b]quinoline-1,3,9-trione was prepared in the following manner: a. 6-Chloro-2-(2-methoxyanilino)-2,3,4,9-tetrahydro-1H-pyrrolo- [3,4-b]quinoline-1,3,9-trione.
  • Example 30 7-Chloro-4-hydroxy-2-(2-methoxyphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quin-oline-1,10-dione.
  • the filtrate saved from Example 30 was diluted with water (600 mL) to give a tan suspension which was stirred at 0 °C for 1 hour and filtered to remove the solids. The filtrate was partially
  • Example 31 7-Chloro-4-hydroxy-2-(2-hydroxyphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quin-oline-1,10-dione.
  • This material was suspended in water (13 mL) and choline hydroxide solution (45 wt% in methanol, 0.5 mL) was added to give a brown solution. This solution was warmed to 50 °C for 2 hours and cooled to room
  • Example 32 7-Chloro-4-hydroxy-3-(3-methoxyphenyl)-3,4,5,10-tetrahydropyridazino[4,5-b]quin-oline-4,10-dione.
  • 6-chloro-2- (3-methoxyanilino) -2,3,4,9-tetrahydro-1H-pyrrolo- [3,4-b]quinoline-1,3,9-trione was prepared in the following manner : a . 6-chloro-2- (3-methoxyanilino) -2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione .
  • Example 33 7-Chloro-4-hydroxy-2-(3-methoxyphenyl)-1,2,5,10-tetra ⁇ hydropyridazino[4,5-b]quin-oline-1,10-dione.
  • the filtrate set aside and saved from Example 32 was diluted with water/ice (1.0 L) to give a brown suspension which was stirred for 16 hours.
  • the suspension was filtered and the collected solids were washed with water and then ether to give the title compound (1.04 g, 56%) as a tan powder, mp 312-315 °C; MS(CI): 370 (M+H).
  • Example 34 7-Chloro-4-hydroxy-2-(3-hydroxyphenyl)-1,2,5,10-tetra ⁇ hydropyridazino[4,5-b]quin-oline-1,10-dione.
  • This material was suspended in water (26 mL) and choline hydroxide solution (45 wt% in methanol, 1.5 mL) was added to give a brown solution. This solution was warmed to 50 °C for 3 hours and cooled to room temperature. Hydrochloric acid (10 mL, IN) was added to give a brown suspension which was filtered. The collected solids were washed with water and then ether to give a brown powder (0.302 g). This brown powder was suspended in methanol and the resulting suspension concentrated to leave a brown solid.
  • Example 35 7-Chloro-4-hydroxy-2-(4-trifluoromethoxyphenyl)-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione.

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Abstract

L'invention porte sur des composés de pyridazinoquinoléine des formules (A) et (A'). Dans ces composés, le noyau A est choisi parmi un cycle aromatique ou hétéroaromatique fusionné en ortho à 5 ou 6 éléments; R4 est choisi parmi un groupe constitué de halo, de (1-4C)alkyle, de NO¿2?, de CN, de (C1-3)perfluoroalkyle, de OH, de OCF3, de (2-4C)alkényle, de (2-4C)alkynyle, de 0(1-4C)alkyle, de NR'R', de SO2NR'R' ou de SOmR'; R?1¿ est choisi parmi de l'hydrogène, du (1-6C)alkyle ou du -(CH¿2?)nL; R?2¿ est choisi parmi de l'hydrogène ou du -(CH¿2?)nL; L représente divers substituants constitués de phényle, de groupes hétérocycliques et de hétéroaryle; n va de 0 à 6; m de 0 à 2, R?5¿ est choisi parmi de l'hydrogène, du (1-6C)alkyle ou du (1-6C)alkylearyle; R3 est choisi parmi de l'hydrogène ou du -(CO)R?6, où R6¿ est choisi parmi divers substituants comprenant de l'hydrogène, du (1-12C)alkyle, du pyridyle, du phényle, du pyridyle (1-12C)alkyle et du phényle (1-4C)alkyle; et R' et R' sont choisis parmi de l'hydrogène, du (1-4C)alkyle, du (3-6C)cycloalkyle, du phényle (0-4)alkyle-, de l'hétérocycle (0-4C)alkyle- ou de l'hétéroaryle (0-4C)alkyle-. L'invention porte également sur des compositions pharmaceutiques comprenant ces substances et sur des procédés destinés au traitement de troubles neurologiques qui en font usage.
PCT/GB1995/002613 1994-11-12 1995-11-08 Composes de pyridazinoquinoleine Ceased WO1996015127A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
DE69526106T DE69526106T2 (de) 1994-11-12 1995-11-08 Pyridazinochinolinverbindungen
MX9703139A MX9703139A (es) 1994-11-12 1995-11-08 Compuestos de piridazinoquinolina.
EP95936046A EP0790996B1 (fr) 1994-11-12 1995-11-08 Composes de pyridazinoquinoleine
AT95936046T ATE215085T1 (de) 1994-11-12 1995-11-08 Pyridazinochinolinverbindungen
AU38132/95A AU705938B2 (en) 1994-11-12 1995-11-08 Pyridazino quinoline compounds
NZ294918A NZ294918A (en) 1994-11-12 1995-11-08 Substituted pyridazino quinoline derivatives and medicaments
JP8515817A JPH10508617A (ja) 1994-11-12 1995-11-08 ピリダジノキノリン化合物
FI971971A FI971971A7 (fi) 1994-11-12 1997-05-07 Pyridatsinokinoliiniyhdisteitä
NO972153A NO308899B1 (no) 1994-11-12 1997-05-09 Pyridazinokinolin-forbindelser, fremgangsmÕte for fremstilling derav og farmasøytisk blanding

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9422894A GB9422894D0 (en) 1994-11-12 1994-11-12 Pyridazino quinoline compounds
GB9422894.7 1994-11-12

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JP (1) JPH10508617A (fr)
CN (1) CN1067685C (fr)
AT (1) ATE215085T1 (fr)
AU (1) AU705938B2 (fr)
CA (1) CA2202135A1 (fr)
DE (1) DE69526106T2 (fr)
FI (1) FI971971A7 (fr)
GB (1) GB9422894D0 (fr)
MX (1) MX9703139A (fr)
NO (1) NO308899B1 (fr)
NZ (1) NZ294918A (fr)
WO (1) WO1996015127A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6103721A (en) * 1993-10-22 2000-08-15 Zeneca Limited Heteroaryl-substituted pyridazino quinoline compounds
WO2001047924A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Procedes et compositions pour le traitement de la douleur
WO2001047923A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Composes et procedes de traitement de la douleur
US6737424B2 (en) * 1995-04-07 2004-05-18 Zeneca Ltd. Alpha-substituted pyridazino quinoline compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0516297A1 (fr) * 1991-05-09 1992-12-02 Zeneca Limited Pyridazine diones et leur utilisation dans le traitement des désordres neurologiques
WO1995011244A1 (fr) * 1993-10-22 1995-04-27 Zeneca Limited Composes de pyridazino quinoleine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0516297A1 (fr) * 1991-05-09 1992-12-02 Zeneca Limited Pyridazine diones et leur utilisation dans le traitement des désordres neurologiques
WO1995011244A1 (fr) * 1993-10-22 1995-04-27 Zeneca Limited Composes de pyridazino quinoleine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6103721A (en) * 1993-10-22 2000-08-15 Zeneca Limited Heteroaryl-substituted pyridazino quinoline compounds
US6737424B2 (en) * 1995-04-07 2004-05-18 Zeneca Ltd. Alpha-substituted pyridazino quinoline compounds
WO2001047924A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Procedes et compositions pour le traitement de la douleur
WO2001047923A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Composes et procedes de traitement de la douleur

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NO972153D0 (no) 1997-05-09
MX9703139A (es) 1997-06-28
EP0790996B1 (fr) 2002-03-27
CN1067685C (zh) 2001-06-27
DE69526106T2 (de) 2002-11-14
JPH10508617A (ja) 1998-08-25
AU3813295A (en) 1996-06-06
NZ294918A (en) 1999-02-25
NO972153L (no) 1997-07-09
EP0790996A1 (fr) 1997-08-27
CA2202135A1 (fr) 1996-05-23
FI971971A7 (fi) 1997-05-12
DE69526106D1 (de) 2002-05-02
GB9422894D0 (en) 1995-01-04
ATE215085T1 (de) 2002-04-15
NO308899B1 (no) 2000-11-13
FI971971A0 (fi) 1997-05-07
CN1171787A (zh) 1998-01-28
AU705938B2 (en) 1999-06-03

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